2. Academic Validation
  3. Small Molecule Neuropilin-1 Antagonists Combine Antiangiogenic and Antitumor Activity with Immune Modulation through Reduction of Transforming Growth Factor Beta (TGFβ) Production in Regulatory T-Cells

Small Molecule Neuropilin-1 Antagonists Combine Antiangiogenic and Antitumor Activity with Immune Modulation through Reduction of Transforming Growth Factor Beta (TGFβ) Production in Regulatory T-Cells

  • J Med Chem. 2018 May 10;61(9):4135-4154. doi: 10.1021/acs.jmedchem.8b00210.
Jonathan Powell 1,  Filipa Mota 2,  David Steadman 2,  Christelle Soudy 2,  Jeremy T Miyauchi 3,  Stuart Crosby 1,  Ashley Jarvis 1,  Tifelle Reisinger 1,  Natalie Winfield 1,  Graham Evans 4,  Aled Finniear 4,  Tamas Yelland,  Yi-Tai Chou 2,  A W Edith Chan 2,  Andrew O'Leary 5,  Lili Cheng 5,  Dan Liu 5,  Constantina Fotinou 6,  Carla Milagre 5,  John F Martin 5,  Haiyan Jia 5,  Paul Frankel 5,  Snezana Djordjevic 6,  Stella E Tsirka 3,  Ian C Zachary 5,  David L Selwood 2
Affiliations

Affiliations

  • 1 NCE Discovery (Domainex Ltd) , Chesterford Research Park, Little Chesterford , Saffron Walden , Essex CB10 1XL , U.K.
  • 2 The Wolfson Institute for Biomedical Research , University College London , Gower Street , London WC1E 6BT , U.K.
  • 3 Department of Pharmacology , Stony Brook University , Stony Brook , New York 11794 , United States.
  • 4 Park Place Research Ltd , Unit 5/6 Willowbrook Technology Park, Llandogo Road, St. Mellons , Cardiff CF3 0EF , U.K.
  • 5 Centre for Cardiovascular Biology and Medicine, Division of Medicine , University College London , 5 University Street , London WC1E 6JJ , U.K.
  • 6 Institute of Structural and Molecular Biology , University College London , Gower Street , London WC1E 6BT , U.K.
PMID: 29648813 DOI: 10.1021/acs.jmedchem.8b00210
Abstract

We report the design, synthesis, and biological evaluation of some potent small-molecule neuropilin-1 (NRP1) antagonists. NRP1 is implicated in the immune response to tumors, particularly in Treg cell fragility, required for PD1 checkpoint blockade. The design of these compounds was based on a previously identified compound EG00229. The design of these molecules was informed and supported by X-ray crystal structures. Compound 1 (EG01377) was identified as having properties suitable for further investigation. Compound 1 was then tested in several in vitro assays and was shown to have antiangiogenic, antimigratory, and antitumor effects. Remarkably, 1 was shown to be selective for NRP1 over the closely related protein NRP2. In purified Nrp1+, FoxP3+, and CD25+ populations of Tregs from mice, 1 was able to block a glioma-conditioned medium-induced increase in TGFβ production. This comprehensive characterization of a small-molecule NRP1 antagonist provides the basis for future in vivo studies.

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